T-Cell MyD88 Is a Novel Regulator of Cardiac Fibrosis Through Modulation of T-Cell Activation
BACKGROUND: Cardiac inflammation in heart failure is characterized by the presence of damage-associated molecular patterns, myeloid cells, and T cells. Cardiac damage-associated molecular patterns provide continuous proinflammatory signals to myeloid cells through TLRs (toll-like receptors) that converge onto the adaptor protein MyD88 (myeloid differentiation response 88). These induce activation into efficient antigen-presenting cells that activate T cells through their TCR (T-cell receptor). T-cell activation results in cardiotropism, cardiac fibroblast transformation, and maladaptive cardiac remodeling. T cells rely on TCR signaling for effector function and survival, and while they express MyD88 and damage-associated molecular pattern receptors, their role in T-cell activation and cardiac inflammation is unknown.
METHODS: We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled wild type versus Myd88-/- mouse T cells at the transcript and protein level and performed several functional assays.
RESULTS: Analysis of single-cell RNA-sequencing data sets revealed that MyD88 is expressed in mouse and human cardiac T cells. MyD88 deletion in T cells resulted in increased levels of cardiac T-cell infiltration and fibrosis in response to transverse aortic constriction. We discovered that TCR-activated Myd88-/- T cells had increased proinflammatory signaling at the transcript and protein level compared with wild type, resulting in increased T-cell effector functions such as adhesion, migration across endothelial cells, and activation of cardiac fibroblast. Mechanistically, we found that MyD88 modulates T-cell activation and survival through TCR-dependent rather than TLR-dependent signaling.
CONCLUSIONS: Our results outline a novel intrinsic role for MyD88 in limiting T-cell activation that is central to tune down cardiac inflammation during cardiac adaptation to stress.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:133 |
|---|---|
| Enthalten in: |
Circulation research - 133(2023), 5 vom: 18. Aug., Seite 412-429 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bayer, Abraham L [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 22.08.2023 Date Revised 10.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1161/CIRCRESAHA.123.323030 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM359931030 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM359931030 | ||
| 003 | DE-627 | ||
| 005 | 20240210232600.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1161/CIRCRESAHA.123.323030 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1286.xml |
| 035 | |a (DE-627)NLM359931030 | ||
| 035 | |a (NLM)37492941 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Bayer, Abraham L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a T-Cell MyD88 Is a Novel Regulator of Cardiac Fibrosis Through Modulation of T-Cell Activation |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 22.08.2023 | ||
| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: Cardiac inflammation in heart failure is characterized by the presence of damage-associated molecular patterns, myeloid cells, and T cells. Cardiac damage-associated molecular patterns provide continuous proinflammatory signals to myeloid cells through TLRs (toll-like receptors) that converge onto the adaptor protein MyD88 (myeloid differentiation response 88). These induce activation into efficient antigen-presenting cells that activate T cells through their TCR (T-cell receptor). T-cell activation results in cardiotropism, cardiac fibroblast transformation, and maladaptive cardiac remodeling. T cells rely on TCR signaling for effector function and survival, and while they express MyD88 and damage-associated molecular pattern receptors, their role in T-cell activation and cardiac inflammation is unknown | ||
| 520 | |a METHODS: We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled wild type versus Myd88-/- mouse T cells at the transcript and protein level and performed several functional assays | ||
| 520 | |a RESULTS: Analysis of single-cell RNA-sequencing data sets revealed that MyD88 is expressed in mouse and human cardiac T cells. MyD88 deletion in T cells resulted in increased levels of cardiac T-cell infiltration and fibrosis in response to transverse aortic constriction. We discovered that TCR-activated Myd88-/- T cells had increased proinflammatory signaling at the transcript and protein level compared with wild type, resulting in increased T-cell effector functions such as adhesion, migration across endothelial cells, and activation of cardiac fibroblast. Mechanistically, we found that MyD88 modulates T-cell activation and survival through TCR-dependent rather than TLR-dependent signaling | ||
| 520 | |a CONCLUSIONS: Our results outline a novel intrinsic role for MyD88 in limiting T-cell activation that is central to tune down cardiac inflammation during cardiac adaptation to stress | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a T lymphocytes | |
| 650 | 4 | |a fibroblasts | |
| 650 | 4 | |a fibrosis | |
| 650 | 4 | |a heart failure | |
| 650 | 4 | |a inflammation | |
| 650 | 7 | |a Myeloid Differentiation Factor 88 |2 NLM | |
| 650 | 7 | |a Receptors, Antigen, T-Cell |2 NLM | |
| 650 | 7 | |a Myd88 protein, mouse |2 NLM | |
| 700 | 1 | |a Smolgovsky, Sasha |e verfasserin |4 aut | |
| 700 | 1 | |a Ngwenyama, Njabulo |e verfasserin |4 aut | |
| 700 | 1 | |a Hernández-Martínez, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Kaur, Kuljeet |e verfasserin |4 aut | |
| 700 | 1 | |a Sulka, Katherine |e verfasserin |4 aut | |
| 700 | 1 | |a Amrute, Junedh |e verfasserin |4 aut | |
| 700 | 1 | |a Aronovitz, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Lavine, Kory |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Shruti |e verfasserin |4 aut | |
| 700 | 1 | |a Alcaide, Pilar |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Circulation research |d 1953 |g 133(2023), 5 vom: 18. Aug., Seite 412-429 |w (DE-627)NLM000001910 |x 1524-4571 |7 nnns |
| 773 | 1 | 8 | |g volume:133 |g year:2023 |g number:5 |g day:18 |g month:08 |g pages:412-429 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1161/CIRCRESAHA.123.323030 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 133 |j 2023 |e 5 |b 18 |c 08 |h 412-429 | ||